Risks of Tight Glucose Control in ICU May Outweigh Benefits

Action Points

Explain that this meta-analysis found that tight control does not reduce death rates and appears to make hypoglycemia, which also has negative consequences, more common.

WHITE RIVER JUNCTION, Vt., Aug. 26 -- Against conventional wisdom, tight glucose control in critically ill patients has not reduced in-hospital death rates. Instead, according to a meta-analysis here, it increases the risk of hypoglycemic episodes.

With data pooled from 27 randomized trials involving 8,315 patients, the relative risk of hospital mortality was 0.93 (95% CI 0.85 to 1.03) for tight glucose control versus usual care, reported Renda Soylemez Wiener, M.D., M.P.H., of the VA Medical Center here, and colleagues in the Aug. 27 issue of the Journal of the American Medical Association.

The American Diabetes Association and several other medical societies have recommended tight glucose control for all critically ill patients, mainly on the basis of a 2001 study that found it reduced hospital mortality among critically ill surgical patients by one-third, said Dr. Wiener and colleagues.

"Subsequent large randomized controlled trials of tight glucose control in medical and mixed medical-surgical ICU settings, however, have failed to replicate this mortality benefit," the researchers said, prompting them to undertake the systematic review.

In an interview, Dr. Wiener said the meta-analysis results warrant a re-evaluation of recommendations of tight glucose control for all ICU patients.

Tight glucose control generally means seeking to keep blood glucose below 150 mg/dL with an insulin infusion during some or all of the ICU stay. Some guidelines, including those endorsed by the ADA, call for glucose levels of 80 to 110 mg/dL.

Studies were included in the meta-analysis if they compared tight control with usual care on a randomized basis and included in-hospital or 30-day mortality, septicemia, new need for dialysis, and/or hypoglycemia as endpoints. They used a total of 29 studies involving 8,432 patients, although not all studies reported all these endpoints.

The pooled-data analysis revealed an overall mortality rate for critically ill patients of 21.6% with tight glucose control versus 23.3% for usual care, with the difference falling short of statistical significance.

Moreover, there were no significant differences in death rates when the results were stratified according to the glucose target (80 to 110 mg/dL versus less than 150 mg/dL) or by the type of ICU (medical, surgical, or mixed).

Nor did tight control appear to have any benefit on the need for new dialysis (relative risk 0.96, 95% CI 0.76 to 1.20).

However, tight control did reduce rates of septicemia, with a relative risk of 0.76 (95% CI 0.59 to 0.97) in the pooled data.

Dr. Wiener said most of this reduction occurred in surgical ICU patients. As a result, tight glucose control may still be appropriate in the surgical ICU.

But counterbalancing this narrow benefit was a dramatically increased rate of hypoglycemia across ICU settings.

The researchers found an overall relative risk of 5.13 for hypoglycemia with tight glucose control (95% CI 4.09 to 6.43), which did not vary significantly for surgical versus medical or mixed ICU patients.

Dr. Wiener said it was unclear why the 2001 study gave such strong results in favor of tight control, other than it focusing on surgical patients.

In that study, she said, patients initially received high levels of glucose and parenteral nutrition that may have created artificial hyperglycemia. Dr. Wiener said that was an unusual practice and could have confounded the results.

But other unknown factors could have played a role or the results may have simply been a statistical anomaly, she said.

The researchers said some recent, large cohort studies not included in the meta-analysis have also failed to find an advantage for tight glucose control.

Dr. Wiener said some of the best data are still to come. A large international study called NICE SUGAR, involving an expected 6,100 patients, should be reported some time next year.

In accompanying editorial, the chief investigator on the NICE SUGAR study and a colleague said the meta-analysis was well-conducted and timely.

Nevertheless, it does not answer every question about tight control, wrote Simon Finfer, M.B.B.S., of the University of Sydney, Australia, and Anthony Delaney, M.B.B.S., of Royal North Shore Hospital in Sydney.

They noted that having a glucose target and actually achieving the target are two different things. Dr. Wiener and colleagues were not able to determine how frequently the targets were met in their included studies, Drs. Finfer and Delaney said.

They also said the respective roles of high blood glucose versus variability of blood glucose in critically ill patients remained to be clarified.

The editorialists noted that NICE SUGAR is unlikely to determine once and for all whether tight control is beneficial or not.

"As patients in the higher range (control) group in NICE SUGAR have their blood glucose controlled to a target of less than 180 mg/dL, even a negative study will not provide evidence in favor of abandoning glucose control," Drs. Finfer and Delaney said.

They also suggested that if it could be demonstrated that tight control is beneficial only under optimal conditions, then the debate should shift to how to provide such conditions.

The meta-analysis was funded by Dartmouth-Hitchcock Medical Center and the Department of Veterans Affairs. No potential conflicts of interest were reported by study authors or the editorialists.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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